The phase II DAISY study evaluated the efficacy of an anti-HER2 drug conjugate, trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer with variable HER2 expression: HER2-overexpressing, HER2-low and HER2 non-expressing cancers. The study suggests that HER2 is a determinant of sensitivity to T-DXd, although modest antitumour activity was also observed in a small subset of patients whose cancer did not express HER2, suggesting other mechanisms of action.
Resistance to T-DXd may occur at different levels, potentially involving decrease of HER2 expression, alterations of the cytotoxic effect of DXd and the tumour microenvironment. The findings are published by Prof. Fabrice André of the Department of Medical Oncology, Gustave Roussy in Villejuif and Faculty of Medicine, Université Paris-Saclay in Kremlin Bicêtre, France, and colleagues on 24 July 2023 in the Nature Medicine.
T-DXd is a third-generation antibody drug conjugate, characterised by a high drug-to-antibody ratio. Although T-DXd provides some clinical benefit in patients with HER2-overexpressing and HER2-low metastatic breast cancer, most of them will ultimately experience disease progression and die. The authors wrote in the background that although the overall structure of T-DXd is well defined, several questions remain regarding its mechanisms of action and resistance. These include the impact of HER2 expression and its spatial distribution on drug efficacy, the distribution of T-DXd in the tumour, the potential impact on the tumour microenvironment, and the molecular mechanisms of resistance.
Understanding the mechanisms of action and resistance could lead to improved treatment selection for patients and the potential development of more effective combinatorial treatment strategies. To address these questions, French investigators designed DAISY, a phase II study that evaluated T-DXd efficacy in patients with metastatic breast cancer according to HER2 expression levels and explored treatment response and resistance through biomarker analyses of tumour samples at different timepoints.
Cohort 1 included 72 patients with HER2-overexpressing, cohort 2 included 74 patients with HER2-low and cohort 3 included 40 patients with HER2 non-expressing metastatic breast cancer. In the full analysis set population of 177 patients, the confirmed objective response rate which was a primary endpoint was 70.6% (95% confidence interval [CI] 58.3–81) in cohort 1, 37.5% (95% CI 26.4–49.7) in cohort 2 and 29.7% (95% CI 15.9–47) in cohort 3. The primary endpoint was met in cohorts 1 and 2.
Secondary endpoints included safety. No new safety signals were observed. The most common adverse effects ≥grade 3 were neutropenia, fatigue and vomiting. Most cases of interstitial lung disease or pneumonitis and decreased ejection fraction in this study were mild or moderate.
During treatment, 4 HER2-expressing tumours presented strong T-DXd staining. Conversely, 3 HER2 immunohistochemistry (IHC) 0 samples presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, p = 0.053). Among patients with HER2 IHC 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8–64.9) with HER2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7–65.2) with HER2 expression above the median.
Although T-DXd antitumour activity increased when HER2 expression was high, modest antitumour activity was also observed in patients with HER2 IHC 0. This suggests that very low levels of HER2 could allow uptake of T-DXd and/or that drug efficacy could be partially mediated by HER2 independent mechanisms. The authors also commented that IHC may not be the optimal test to define the boundary of HER2 expression to predict efficacy in patients with HER2-low metastatic breast cancer.
The authors concluded that DAISY findings point out to converging evidence that HER2 expression is a determinant of T-DXd efficacy although modest antitumour activity was also observed in a small subset of patients whose cancer did not express HER2, suggesting other mechanisms of action. Precision medicine approaches based on molecular analyses will be necessary to optimise treatment after resistance to T-DXd.
Reference
Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nature Medicine; Published online 24 July 2023. DOI: https://doi.org/10.1038/s41591-023-02478-2
